The compound known under the generic name omeprazole is described in European patent 0005129. Further, European Patent No. 124,495 describes the advantages of providing the salts of omeprazole and particularly the magnesium salt thereof.
Omeprazole is useful for inhibiting gastric acid secretion and has gastric mucosa protective activity in mammals and man. Omeprazole may be used for prevention and treatment of gastric acid related disorders and gastrointestinal inflammatory diseases in mammals and man, including for example gastritis, gastric ulcer and duodenal ulcer.
The terms “omeprazole, S-omeprazole and R-omeprazole” as used in this specification designate the neutral form thereof, that is the form without a salt-forming cation present, unless otherwise indicated.
European Patent No. 0124495, in example 5 specifically discloses the synthesis of magnesium omeprazole dihydrate, and example 6 specifically discloses the synthesis of magnesium omeprazole anhydrate. Manufacturing of the described magnesium omeprazole salt presents significant difficulties.
The process of manufacture and isolation of the dihydrate according to example 5 is relatively complex. It requires making the sodium salt, adding a solution of magnesium chloride to obtain a precipitate, removing water by centrifuging the precipitate, washing the precipitate with deionized water until no Cl− is detectable, drying in air, grinding, and then drying in vacuum at 40° C. for 24h. Moreover, because the resulting magnesium omeprazole dihydrate is crystalline, the rate of dissolution in intestinal fluid is relatively slow, unless the material is milled to a relatively fine particle size. It would therefore be desirable to provide non-crystalline forms to improve the dissolution in intestinal fluid.
The process of making the anhydrate according to example 6 is simpler. Magnesium is reacted with methanol to give a solution of magnesium methoxide in methanol. The solution is added to a solution of omeprazole in methanol, the quantity of omeprazole being one mole for each two moles of magnesium. The methanol is then evaporated to give a crystalline solid, which is magnesium omeprazole anhydrate. However, the anhydrate as made by this process is also not without a problem. As the magnesium omeprazole precipitates from the solution upon evaporation of the methanol, residual methanol is entrapped in the solid particles and cannot easily be removed by evaporation. Methanol is toxic and high levels are generally considered unacceptable in pharmaceutical chemicals.
Canadian patent 2166794 describes what is said to be an improved form of magnesium omeprazole dihydrate, which has a higher degree of crystallinity than that of example 5 of EP 0124495. This form has a methanol content of less than 0.1%. However, like the product of example 6 of EP 0124495, it is a crystalline dihydrate, and the process of manufacture is relatively complex.
According to Canadian patent 2166794, the degree of crystallinity of a sample made according to example 6 of EP 0124495 was 67%, whereas the degree of crystallinity of the improved form is at least 70%.
Canadian patent application No. 2254572 discloses improved processes for the production of magnesium omeprazole crystalline dihydrate. The disclosure reviews the prior art, and in particular, in relation to the anhydrate of example 6 of EP 0124495, states as follows: “This procedure cannot be practiced on a large scale because of the need to evaporate to dryness. It has been found that unacceptable and potentially dangerous amounts of methanol become trapped in this solid, making it pharmaceutically unacceptable.” The processes of Canadian patent 2254572 are again relatively complex.
Improved processes for the production of magnesium omeprazole crystalline dihydrate are also described in PCT Publication No. WO 97/41114. The degree of crystallinity of the product of example 1 is said to be 80%. Again, the processes disclosed are relatively complex.
Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom is the stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, the R and S-enantiomer of omeprazole, herein referred to as R-omeprazole and S-omeprazole. The absolute configurations of the enantiomers of omeprazole have been determined by an X-ray study of an N-alkylated derivative of the (+)-enantiomer in non-salt form. The (+)-enantiomer of the non-salt form and the (−)-enantiomer of the non-salt form were found to have R and S configuration, respectively, and the (+)-enantiomer of the magnesium salt and the (−)-enantiomer of the magnesium salt were also found to have R and S configuration, respectively. The conditions for the optical rotation measurement for each of these enantiomers are described in WO 94/27988.
Certain salts of single enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation.
WO 96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and salts thereof, and WO 96/01623 discloses a suitable tableted dosage form for instance magnesium salts of R- and S-omeprazole. The magnesium salt of S-omeprazole trihydrate described is substantially free from magnesium salts of R-omeprazole.
U.S. Pat. No. 5,714,504 describes optically pure salts of omeprazole and in particular the sodium and magnesium salts thereof as pure crystalline enantiomeric salts, and in one embodiment optically pure crystalline magnesium salts. The patent describes the non-aqueous process for the preparation of crystalline forms of the magnesium salts of optically pure enantiomers of omeprazole or analogues thereof; which include the steps of stirring a crude preparation of the omeprazole enantiomer under nitrogen into a methanolic magnesium methoxide solution, precipitating inorganic magnesium salts with the addition of a small amount of water, removing any precipitated inorganic magnesium salts, concentrating the residual methanolic solution, precipitating the omeprazole enantiomer by adding acetone to the residual solution, and filtering off the optically pure enantiomer crystals of magnesium omeprazole or analogues thereof. Because it is possible to purify optically impure or partially pure salts of the enantiomers of omeprazole by crystallization, they can be obtained in very high optically pure, namely greater than or equal to 99.8% enantiomeric excess. Example 6 within the specification describes the preparation of the magnesium salt of S-omeprazole by crystallization of said salt.
The preferred enantiomer of omeprazole referred to as the (−)-enantiomer of omeprazole or a pharmaceutical salt thereof, is said to be an improved alternative to omeprazole in the treatment of gastric acid related diseases which provides higher dose efficiencies and less inter-individual variation in plasma levels, both between rapid and slow metabolizers and within the group of rapid metabolizers, as taught in U.S. Pat. No. 5,877,192. The major emphasis described relates to various forms of the enantiomers of omeprazole and salts thereof in crystalline form and preferably in highly crystalline form, which are also described in Canadian Patent Application No. 2,357,744. Although amorphous forms are nominally discussed there is no specific teaching as to the advantages of preventing crystals from forming. Therefore, a need exists for the magnesium salts of enantiomers of omeprazole having a desirable low methanol content.
U.S. Pat. No. 6,262,085 teaches in example 20 the magnesium salt of S-omeprazole. Generally, the patent describes the preferred crystalline form but states that other forms such as amorphous forms are casually mentioned, but clearly the teaching refers to crystalline and particularly to the co-crystalline form wherein enantiomers of omeprazole are present in the same crystal lattice and co-crystallized from solution. However, there is no teaching as to the manner in which amorphous forms in particular might be prepared, resulting in the same deficiencies with reference to solvent content as described above.
It would therefore be highly desirable to provide primarily amorphous magnesium salt of the enantimers of omeprazole and particularly the magnesium salt of S-omeprazole, since these salts have surprisingly high stability in alkaline conditions. There still exists a need for magnesium salts of enantiomers of omeprazole having substantially low methanol content and having a minimum amount of crystallinity with a large percentage of the material being amorphous, that is having minimum crystalline structure.
In summary, the only magnesium omeprazole according to the prior art that has an acceptably low level of methanol is magnesium omeprazole crystalline dihydrate, which has a degree of crystallinity of 67% or higher and is produced only by relatively complex processes.
In light of the foregoing, the object of the present invention is to produce magnesium omeprazole and the magnesium salt of enantiomers of omeprazole having acceptably low levels of methanol, but containing a large proportion of amorphous material (non-crystalline), which preferably may also be substantially amorphous as well, to be produced by a simple process.
It is also an object of this invention to provide the magnesium salt of S-omeprazole in pharmaceutically acceptable forms.
It is a further object of the invention to provide the magnesium salt of R-omeprazole in pharmaceutically acceptable forms.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the preferred embodiments and examples contained herein.